3-acylamino-2-omega-r-alkyl-4-thiophenecarboxylic acid hydrazides



Patented Apr. 4, 1950 UNITED STATES PATENT OFFICE 3-ACYLAMIN0-2-w-R-ALKYL-4-THIOPHENE CARBQXYLIC ACID HYDRAZIDES Lee C. Cheney, Syracuse, N. Y., and John Robert Piening, Detroit, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Original application December 23,

1944, Serial No. 569,640. Divided and this application April 8, 1946, Serial No. 660,403

follows o o a o ONHNH: 1 IYIHC OR I NH-C OR" OO H2NNH2.H2O b- II II I II HO CC "Eh-R use of alkaline HO C-G Han-R medium, with S or w i t h o u t S su b se q u e n t acidification Where R is a radical of the class COOH, -COOM,. alkoxy, aralkoxy and aryloxy, M is a salt-forming basic group or metal such as sodium or other alkali metal, alkaline earth metal, magnesium, ammonium and substituted ammonium, such as monoalkylammonium and dialkylammonium, R. is lower alkyl, -COR" is an organic carboxylic acid acyl radical and n is an integer from 1 to 8. The 3 acylamino 4 carboalkoxy 2 w R- alkyl thiophenes are prepared by acylating the 3- amino-4-carboalkoxy-2-w-R-alkyl thiophenes as described in our parent application Serial No. 569,640 and claimed in our copending divisional application Serial No. 660,402, filed AprilB, 1946. These latter compounds may be prepared by methods disclosed in our copending application Serial No. 569,639, filed December 23, 1944, now Patent No. 2,443,598, issued June 22, 1948.

The following examples illustrate the invention.

Example 1 3 benzoylamino 4 carbethoccy 2 thiophenevaleric acid.A cooled solution of 2.71 g. (0.01 mole) of 3amino-4-carbethoxy-2-thiophenevaleric acid in 25 ml. of dry chloroform is treated with 1.4 ml. of benzoyl chloride. The mixture is protected by a calcium chloride tube and refluxed on the steam bath for 24 hours. Following removal of solvent by steam distillation, the residual brown oil is dissolved in ether,

4 Claims. (Cl. 260-329) and the ether solution is extracted thrice with 5% sodium bicarbonate solution. The combined alkaline extracts are cooled, acidified to Congo red with dilute hydrochloric acid and extracted twice with ether. Combined ether extracts are dried with anhydrous sodium sulfate, the ether is evaporated and the residue is shaken with 200 ml. of petroleum ether (B. P. 35-60 C.) for the removal of benzoic acid. The resulting light tan solid is filtered. Recrystallization from dilute alcohol yields 2.77 g. (81%) of cream-colored needles, M. P. 126.5-127.5 0., having the formula H II no ooizmlooon AnaZ.-Calcd. for C19I-I21O5NS: C, 60.77; H, 5.63; Found: C, 60.70; H, 5.53.

3 benzoylamino-2-A-carb0mybutyZ-4-thiophenecarboxylic acid hydraeide.A mixture of 1.10 g. (0.00293 mole) of 3-benzoylamino-4-carbethoxy- 2-thiophenevaleric acid and 0.308 g. (0 .00308 mole) of potassium bacarbonate. is warmed with 25 ml. of 50% alcohol until solution is complete. Solvent is distilled at reduced pressure, leaving the potassium salt which is desiccated overnight in vacuo over phosphorus pentoxide. This dry salt is dissolved in 10 ml. of warm absolute alcohol, treated with 10 ml. of dry benzene and 2 ml. of hydrazine hydrate, protected by a calcium chloride tube and refluxed on the steam bath for 16 hours under a Soxhlet extractor containing 25 g. of anhydrous calcium sulfate in its thimble. Solvent and excess hydrazine hydrate are distilled at reduced pressure, leaving a fluffy mixture consisting mainly of the potassium salt of 3 benzoylamino 2 A carboxybutyl 4 thiophenecarboxylic acid hydrazide along with some potassium salt of unchanged 4-carbethoxy compound. The mixture is dissolved in 30 ml. of water. A yellow aqueous solution is obtained which can :be mixed with inert Water immiscible organic solvent, such as ether, and then acidified with a lower aliphatic carboxylic acid, suchas acetic .or propionic acid, whereby unchanged starting material goes into the ether solution but the desired 4-thiophenecarboxylic acid hydrazide is insoluble in the ether as well as the aqueous phase and can be filtered off. Thus, the yellow solution is covered with 30 ml. of ether and is made almost neutral to litmus with 5% hydro chloric acid solution. The ether of the resulting mixture serves to dissolve unchanged 4-carbethoxy starting material. The mixture is acidified II HG C-(CHaMCOOH AnaZ.-Calcd. for C1'1H190'4N3S2 C, 56.49; H, 5.30. Found: C, 56.40; H, 5.57.

In this example water is liberated when the hydrazine hydrate reacts. The water liberated is quickly carried into the refluxing vapors and by them into contact with the anhydrous calcium sulfate in the thimble and. thereby removed from the reactants. The mixture of dry benzene with alcohol facilitates the removal of the water. Such procedure for removing water is important, since its use almost doubles the yield of hydrazide over that obtained when using alcohol in the absence of the benzene and the anhydrous calcium sulfate.

Example 2 Ethyl 3-benzoylamz'no 2 -phenoaypropylA- thiophcnecarboxyZate.To a warm solution of 14.1 g. (0.046 mole) of 3-amino-4-carbethoxy-2- v-phenoxypropylthiophene, M. P. 56-57 C. in 100 ml. of glacial acetic acid is added 100 ml. of a saturated solution of sodium acetate. The wellstirred suspension is cooled in an ice bath and 8 ml. (9.7 g.) (0.069 mole) of benzoyl chloride is added-dropwise. Lumps of solid soon separate. After stirring for 40 minutes the suspension is filtered and washed with ice water. The granular product is dissolved in 180 ml. of hot glacial acetic acid, treated with 70 ml. of a saturated solution of sodium acetate, cooled in ice and again treated with 8 ml. of benzoyl chloride. As soon as the suspension solidifies the ice bath is removed, 50 ml. of water is added and the mixture is stirred at room temperature for 3.5 hours. Then 100 ml. of water is added and the suspension is cooled, filtered, washed with cold water and desiccated in vacuum over P205. Crystallization from alcohol following Darco treatment produces 15.7 g. (83% yield) of fine ivory crystals, M. P. 97-98 C. A sample of the compound is recrystallized from alcohol (Darco) as colorless needles, M. P. 98-99 C.

Anal.-Calcd. for C23H23O4NSZ C, 67.5; H, 5.66. Found: C, 67.38; H, 5.91.

Its formula is,

3 benzoylamz'no 2- 'y phenoxypropyZ-4-thiophenecarbomylic acid hydrazide --A mixture of 14.6 g. (0.0357 mole) of ethyl 3-benzoylamino-2- v phenoxypropyl 4 thiophenecarboxylate, 100 ml. of absolute alcohol and 25 ml. of 85% hydrazine hydrate is refluxed for 16 hours on the steam bath. During the night white crystals separate from solution. After removal of excess hydrazine by distillation at reduced pressure, the crystalline mass is boiled with about 700 ml. of

4 absolute alcohol, cooled in an ice-salt bath and filtered. Following desiccation the fine lustrous crystals melt at 1865-1875 C. The yield is 13.1 g. or 93% of the theoretical.

Anal.Calcd. for C21I-I21O3N3S: C, 63.8; H, 5.34. Found: C, 63.77; H, 5.29.

Its formula is,

Ewample 3 Ethyl 3-benzoylamino-z- -benzylowypropybeithiophenecarbomyZata-A mixture of 2.79 g. (0.00875 mole) of 4-carbethoxy-3-amino-2-vbenzyloxypropylthiophene 13 ml. of dry chloroform and 1.2 ml. of benzoyl chloride is refluxed on the steam bath for 17 hours. The chloroform is removed by steam distillation. The water is poured from the oil after cooling. The oil is dissolved in alcohol and is given a treatment with Darco. The alcohol solution is concentrated after filtering from Darco and is treated with hot water until a faint turbidity remains. When cool, an oil separates out. Addition of a large volume of water precipitates more oil. After scratching and cooling for several hours the product begins to crystallize, yielding a tan material which is collected, dried and weighed. The weight of crude material is 3.4 g., yield 92%, M. P. 60 C. A sample is recrystallized three times from ethanol to a melting point of 65-66" C.

AnaZ.Ca1cd. for C24H2504NS: N, Found: N, 3.44%.

Its formula is,

3-benzoylamino 2 -benzylomypropyZ-4-thiophenecarb xi/lic acid hydrazide.-A mixture of 2.96 g. (0.0007 mole) of 4-carbethoxy-3-benzoylamino-2-' -benzyloxypropylthiophene, 20 ml. of absolute alcohol and 5 ml. of hydrazine hydrate is refluxed on the steam bath for 16 hours. The solution is cooled in an ice bath. After several hours a fiocculent mass of crystals has formed. These are collected and dried. Weight, 0.64 g., M. P. 116-117 C. The filtrate is warmed and diluted with a large volume of water. Cooling and stirring produces further crystals of crude hydrazide. Weight, 1.89 g.

Anal.--Ca1cd. for C22H2303N3S2 N, 10.26%. Found: N, 10.07%.

Its formula is,

hydrothiophenevalerate by treatment of a dry ether solution of the latter withidry hydrogen chloride gas, converting the amine hydrochloride to the amine with alkali bicarbonate, and finally partially hydrolyzing the amine to the monoester. The oxime mentioned is made from ethyl 4-carbethoxy 3 keto 2 -tetrahydrothiophene-' valerate and hydroxylamine hydrochloride by the known procedure for producing oximes from their corresponding ketones. The 3-keto'compound is, in its turn, made from the action of dry sodium ethylate in dry benzene on fi-carbethoxyethyl a,w-dicarbethoxyamyl sulfide of formula,

a solution of sodio ethyl malonate with ethyl A-chlorovalerate and hydrolyzing the tri-ester obtained into A-carboxybutylmalonic acid. thereafter using sulfuryl chloride to convert the butylmalonic acid compound to A-carboxybutylchloromalonic acid which can be decarboxylated by heat to a-chloropimelic acid of formula,

All of the above reactions for making the intermediate of Example 1 and also analogous in--.

termediates for the other examples are described in United States applications of Lee ,C. Cheney and John Robert Piening, Serial No. 550,483 and Serial No. 550,484, filed August 21, 1944, both now abandoned, and Serial No. 551,619, filed August 28, 1944.

Numerous variations from the above examples, which are nevertheless within the scope of the invention, will occur to those skilled in the art. For example, in the first step wherein the 3- amino group is converted to an amide group, any suitable organic carboxylic acid acylating agent may be used, such as acetyl chloride, acetic anhydride, phenyl acetyl chloride, .naphthoyl chloride as well as benzoyl chloride.

6 What we claim as our invention is: 1. A 3-acylamino-2-(w-R-substituted alkyll-fithiophene-carboxylic acid hydrazide of forni a,

c ONHNH: T

where the alkyl chain, CnH2n-, consists. at

from 1 to 8 carbon atoms, where R is a radical of the class consisting of COOH, COQllQ;

alkoxy, aryloxy and aralkoxy, M is a salt-form ing basic group and COR" is an organic car-- boxylic acid acyl radical.

2. A compound of the formula,

CONHNH:

NH-COOQE H onopo OOH 3. A compound of the formula,

CONHNH:

NH-OO 0.11.

Hy Hl-(CHzh-Q-CoHa 4. A compound of the formula,

OONHNH;

NH=O O CIHI II a HO (O Hz)r-OO HIOIHI LEE C. CHENEY. JOHN ROBERT PIENILNG.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Schnider Mar. 11, 1947 OTHER REFERENCES Number 

1. A 3-ACYLAMINO-2 (W-R-SUBSTITUTED ALKYL)-4THIOPHENE-CARBOXYLIC ACID HYDRAZIDE FOR FORMULA, 